Sciencemadness Discussion Board

Preparation of N-Bromosuccinimide

AvBaeyer - 28-1-2019 at 19:50

A Preparation of N-Bromosuccinimide

Introduction

Some experimental work currently in progress required a sample of N-bromosuccinimide (NBS) to test as a bromination reagent compared to 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). This comparison was necessary since pure DBDMH has been withdrawn from the OTC marketplace [1]. Moreover, NBS is a very useful reagent to use in a variety of reactions and so finding a reliable and safe method for its small scale preparation seemed a useful undertaking.

The preparation of NBS is most commonly carried out by the addition of elemental bromine to an alkaline solution of succinimide in water [2]. In the home laboratory this method requires the preparation, purification and handling of elemental bromine. This is outside the scope of the safety parameters that I adhere to in my laboratory. However, I was aware of a number of publications which report the bromination of various organic compounds using in situ generated bromine derived from sodium or potassium bromide and a suitable oxidizing agent. A literature search [3] produced three references for the bromination of amides or imides with in situ generated bromine. One procedure uses an oxone-halide ion system to generate halogen for preparing N-halosaccharins [4]. Two others use a bromate-bromide system to generate bromine and N-bromoamides [5, 6]. Importantly, all of these procedures use aqueous based reaction media. This report deals with the bromate-bromide chemistry presented in references 5 and 6.

The stoichiometry of the chemical reaction under consideration [5, 6] is the following where “>NH” represents the amide or imide to be halogenated:

6>NH + 2NaBrO3 + 4NaBr + 6H(+) --> 6>N-Br + 6Na(+) + 6H2O

The experimental methods described in both papers are different in terms of molar reagent ratios and reagent addition methods. The Fujisaki paper [5] uses the following molar ratio of reagents (method B):

>NH: NaBrO3: NaBr: H(+) = 3: 1.5: 2: 4.5

The molar reagent ratios in the Adimurthy paper are:

>NH: NaBrO3: NaBr: H(+) = 3: 2: 1: 3

In both papers the acid source is sulfuric acid.

The Fujisaki paper makes no mention of temperature control of the reaction and adds NaBr as a solid to the reaction. The Adimurthy procedure runs the reaction at 10-15C and adds the required acid over an extended period. My aim was to repeat these experiments and, if necessary, find useful modifications suitable for the home laboratory.

Results and Discussion

All experiments were run on 5.0g (50 mmoles) of succinimide. This allowed a more realistic comparison of yields across methods.

The first procedure to be repeated was that of Fujisaki (Method B) which uses 70% acetic acid as the reaction solvent. The initial experiment was run at room temperature and involved the slow addition of solid NaBr to the reaction mixture. The reaction was quite exothermic and evolved considerable bromine fumes. The yield of NBS was quite poor. When the reaction was run with cooling (ca 10-15C) and temperature monitoring, the portion wise addition of solid NaBr caused temperature spikes to 20C and evolution of bromine fumes. The cooled reaction provided NBS in about 50% yield after recrystallization.

The Adimurthy procedure was next repeated. In this procedure sulfuric acid is added very slowly (ca 1 -2 hr) to a water solution of the other reagents with attention to temperature control. This procedure provided NBS in 72% yield after recrystallization. The advantage of this method is the use of water as the only solvent. The major disadvantage is the slow addition of ca 50% sulfuric acid which in my case took about 75 minutes. If the acid is added too rapidly a temperature spike occurs and bromine vapor is released.

Several additional experiments were run to test various alternate reaction conditions. In the end, a hybrid method was developed which has worked consistently well and is based on the reagent ratios used by Fujisaki. The method uses only water as the solvent, sodium bisulfate as the acid source and the slow addition of a water solution of NaBr to a chilled reaction mixture. Because bromine is being generated, a well ventilated space is necessary in the event that bromine vapor is produced. Sodium bisulfate was chosen as the acid source because it can be obtained in a quite pure state OTC and can be easily handled. It is a better choice than hardware store sulfuric acid which likely contains impurities which may adversely affect the reaction. I believe the described method is safe to use in the home laboratory paying attention to usual safety standards and exercising patience when running the reaction.

Experimental

Succinimide and sodium bromate were from HiMedia. Sodium bromide and sodium bisulfate monohydrate (93% purity) were standard pool chemicals obtained locally. All chemicals were used as received. A strong magnetic stirrer is required as the reaction gets quite thick near the end. The reaction vessel was a 150 ml Erlenmeyer flask into which was suspended a thermometer to monitor the reaction temperature which is kept at ca 10C.

Sodium bisulfate monohydrate (11.12 g, 93% pure, 75 mmole) is dissolved in water (35 ml) then chilled in an ice bath to ca 10C. Sodium bromate (3.78 g, 25 mmole) is added followed by succinimide (5.0 g, 50 mmole). Most solids dissolve after a few minutes of stirring at 10C. Sodium bromide (3.45 g, 33.5 mmole) is dissolved in water (10 ml) which is then added with a dropper 5-7 drops at a time. Follow on additions are made when the bromine is consumed as indicated by the return of the reaction mixture to a white color. After about 20% of the sodium bromide solution has been added, NBS begins to precipitate. Once the precipitation starts, the time interval for bromine consumption lengthens [7]. The total time required for sodium bromide addition is about 1 hour after which the reaction is stirred for an additional hour in the ice bath. At this point the mixture is very thick. The cold reaction mixture is then filtered under vacuum. The reaction flask is rinsed with ice water (20 ml) and the solid washed with additional ice water (20-30 ml) until it is white. The solid is sucked as dry as possible on the filter but remains a thick paste [8].

In order to obtain a pure crystalline product, the paste is added to well stirred water (65 ml) heated to 80C - 85C. Additional hot water (15- 20 ml) is added dropwise until nearly all the solids have dissolved [9]. The heating time should be short (ca 5 min or less) to minimize decomposition of the NBS [10]. The hot solution is then rapidly filtered into a flask chilled in an ice bath (a coffee filter works well here.) The filtrate is rapidly chilled by swirling in the ice bath then kept in the ice bath for about 1 hour. Filtration affords white crystals which are first dried by suction then in the dessicator over calcium chloride for 24 hours. Typically, from 5.0 g of succinimide 5.5g to 6.5g (62% – 73%) of recrystallized NBS are obtained [9] with mp 180-182C [11].

The product should be stored in the dark in a cool place. Further drying under vacuum at 40C may be required for use in some reactions.

The aqueous filtrates and washings generated above contain bromine which should be destroyed by the addition of sodium bisulfite or sodium thiosulfate before disposal.

References and Notes

1. https://www.sciencemadness.org/whisper/viewthread.php?tid=71...
2. D. A. Shirley, “Preparation of Organic Intermediates”, J. Wiley and Sons, 1951, p. 59
3. Using only Google/Google Scholar
4. S.P.L. de Souza, et. al, Syn. Commun. 2003, 33, 935-939
5. S. Fujisaki, et. al, Bull. Chem. Soc. Japan 1993, 66, 2426-2428.
6. S. Adimurthy, et. al, Green Chem. 2006, 8, 916-922.
7. Patience is important here. If bromine vapors are observed, the addition rate is too fast.
8. Attempts to air dry the paste on filter paper led to discoloration of the product after several hours. Thus, immediate recrystallization is appropriate as the crystalline product is much easier to handle.
9. The total volume of water used in ml should not be greater 9-10 times the theoretical weight of pure product. A clear solution is not always obtained. The undissolved solids after drying are usually quite pure NBS (mp 180-182C) and can account for 10-15% of additional yield.
10. Prolonged heating leads to a deep yellow solution indicating decomposition of the NBS. It is better to leave some material undissolved rather than prolong heating. See [9].
11. The mp of NBS is not an absolute criterion of purity as it can be somewhat variable. If one wants to know the true purity of the product an iodometric titration must be done.

AvB


Attachment: Bromination reagent- NaBr+NaBrO3 adimurthy2006.pdf (290kB)
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Attachment: N-Bromo imides and amides using NaBrO3 fujisaki1993.pdf (284kB)
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Metacelsus - 28-1-2019 at 23:42

Good work! What are you planning to do with your NBS next?

AvBaeyer - 29-1-2019 at 19:33

Thanks, Metacelsus. I never intended to make a project out of this!

After all the experimental variations I now have at least 80 grams of NBS. I started this simply needing only enough NBS to compare its reactivity vs DBDMH in an Appel reaction where DBDMH does not behave as anticipated. There is no head to head test like this that I can find in the literature. Data from the head to head tests will be forthcoming shortly.

AvB

DavidJR - 30-1-2019 at 02:39

Maybe it'd be worth trying tribromoisocyanuric acid.

AvBaeyer - 30-1-2019 at 11:51


Why should I try tribromoisocyanuric acid? You cite nothing in support of your suggestion and thereby add nothing to the discussion. It’s just pissing in the wind like a whole lot of “suggestions” made on this board. Find a reference related to the Appel reaction or do the experiment and tell me about it. I am not so unschooled that I could not come up with a comprehensive list of N-bromo alternatives but that is not the point. My reply to Metacelsius was quite clear. I want to compare NBS with DBDMH in a very specific reaction, the EXPERIMENTAL results of which will be reported in due course.

AvB

DavidJR - 30-1-2019 at 12:15

Quote: Originally posted by AvBaeyer  

Why should I try tribromoisocyanuric acid? You cite nothing in support of your suggestion and thereby add nothing to the discussion. It’s just pissing in the wind like a whole lot of “suggestions” made on this board. Find a reference related to the Appel reaction or do the experiment and tell me about it. I am not so unschooled that I could not come up with a comprehensive list of N-bromo alternatives but that is not the point. My reply to Metacelsius was quite clear. I want to compare NBS with DBDMH in a very specific reaction, the EXPERIMENTAL results of which will be reported in due course.

AvB


In the first paragraph of your original post, you say the motivation behind this is to find a useful replacement for previously-OTC DBDMH. Not to perform a very specific reaction.

I suggested tribromoisocyanuric acid because the cyanuric acid needed to prepare it is available a lot more readily and cheaply than succinimide is - cyanuric acid is available online as a chlorine stabilizer for swimming pools, and I imagine in a geographical location where home pools are common, that it is also available in stores.


clearly_not_atara - 30-1-2019 at 13:03

There are reports of making succinimide by heating succinic acid and urea; with catalytic metal oxides the reaction has been reported as low as 160 C.

They haven't been tested by SM members, but now that AvBaeyer has shown how to get from succinimide to NBS, I think there's a better motivation to try to verify said reports.

However, what I don't have is a way of making sodium bromide from CBDMH that doesn't involve either elemental bromine or Co(NH3)6(3+), the latter apparently being out of reach for some users.

[Edited on 30-1-2019 by clearly_not_atara]

Metacelsus - 31-1-2019 at 04:10

Quote: Originally posted by clearly_not_atara  

However, what I don't have is a way of making sodium bromide from CBDMH that doesn't involve either elemental bromine or Co(NH3)6(3+), the latter apparently being out of reach for some users.


I'm not sure this is much of an issue, given that sodium bromide is generally available to the amateur chemist (it's sold for hot tub treatments). There's no need make it from CBDMH.

Or did you mean bromate? Bromate can be obtained by electrolysis of bromide (although the electrolysis tends to degrade MMO anodes, so don't use those).

morganbw - 31-1-2019 at 06:49

Nice write up. It is a pleasure to read a well presented and thought out experiment. Thank you for your time.

AvBaeyer - 1-2-2019 at 09:53

DavidJR,

"I suggested tribromoisocyanuric acid because the cyanuric acid needed to prepare it is available a lot more readily and cheaply than succinimide is...."

This is getting tedious. Have you any idea as to how bromination of isocyanuric acid is done? Check it out as an exercise in literature searching then do the experiment. Again, nothing is added to the discussion.

Enough.

AvB

karlos³ - 8-9-2019 at 07:50

I made N-chlorosaccharin via NaCl and oxone in water, I wonder if it would be possible to do the same with succinimide to get NCS?

Boffis - 9-9-2019 at 10:49

@karlos. Are you going to give use a reference/details/experimental results?

karlos³ - 9-9-2019 at 12:01

For the N-chlorosaccharin synthesis? I can get the reference for that reaction, yes.

Or do you mean for an attempt of NCS via the same path?
I believe that won't work as good as it did for the saccharin analogue, due to the solubility of NCS in water...
As the synthesis is done in plenty of water, and I wouldn't dare to use less, as some chlorine still escaped during the course of the synthesis.

Here is the reference I used for the N-chlorosaccharin preparation: green prep halosaccharin